Cardiovascular diseases are among the leading causes of mortality and morbidity worldwide with ever-increasing prevalence. Cardiovascular diseases include numerous conditions that affect the heart, heart valves, blood, and blood vessels (arteries, capillaries, and veins) of the body. The causes of cardiovascular disease are diverse but atherosclerosis and/or hypertension are the most common. Risk factors include elevated plasma total or LDL cholesterol, elevated triglycerides, low HDL cholesterol, e.g. hyperlipidemia, hypercholesterolemia, or hypoalphalipoproteinemia, and increased inflammatory markers such as C-reactive protein and fibrinogen.
Major cardiovascular diseases including stroke, atherosclerosis, and hypertension, as well as orphan diseases such as pulmonary hypertension, angiosarcoma, hemangiosarcoma, and hypertrophic cardiomyopathies, are incurable. In addition, medical therapies to treat congestive heart failure and pulmonary hypertension-associated heart failure are inadequate.
Pulmonary hypertension presents an increase of blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, leg swelling and other symptoms. Pulmonary circulation is a low resistance, low pressure, and high compliant vascular bed. In pulmonary hypertension, the pressure in the pulmonary artery rises above normal levels. Normally, pulmonary artery pressure is maintained around 20-25 mmHg. Pulmonary hypertension is defined when the pressures increase to more than 30 mmHg. Pulmonary hypertension is a major cause of morbidity and mortality in patients with several different clinical conditions. Pulmonary hypertension is a progressive disease and the pathophysiology of pulmonary hypertension is heterogeneous. Severe pulmonary hypertension remains debilitating and deadly. Pulmonary hypertension is divided into five groups with diverse etiologies. In all forms of pulmonary hypertension, pulmonary artery pressure increases mainly because of increased pulmonary constriction/resistance and narrowing or remodeling of pulmonary artery and veins. One cause of pulmonary hypertension is alveolar hypoxia, which results from localized inadequate ventilation of well-perfused alveoli or from a generalized decrease in alveolar ventilation. Pulmonary hypertension is also a vascular permeability related disease. Current therapies are inadequate to reverse the complex pulmonary vascular remodeling and reduce pulmonary vascular resistance. Pulmonary hypertension has been historically chronic and incurable with a poor survival rate. Treatment of pulmonary hypertension usually involves continuous use of oxygen. Pulmonary vasodilators (e.g., hydralazine, calcium blockers, nitric oxide, protein kinase G activators, prostacyclin, endothelin receptor blockers) have not proven effective, and lung transplant is often required for patients who do not respond to therapy.
Arteriosclerosis, which is induced and progressed by various risk factors, causes thickening of the arterial lumen to interrupt blood flow, resulting in a cardiovascular disease such as aortic aneurysm, angina, myocardial infarction, or cerebral infarction.
Cardiac hypertrophy is an adaptive response of the heart cells to elevated levels of biomechanical stress imposed by a variety of extrinsic and intrinsic stimuli including pressure or volume overload, familial/genetic cardiomyopathies, or loss of contractile mass from preceding infarction (Frey et al. (2004) Circulation 109:1580-1589; Frey et al. (2003) Annu. Rev. Physiol. 65:45-79; Yoshida et al. (1986) J. Cardiogr. 16:399-406). If sustained, hypertrophy often becomes pathological, accompanied by significant risk of arrhythmia, progression to heart failure, and sudden death (Frey et al. (2004), supra; Levy et al. (1990) N. Engl. J. Med. 322:1561-1566; Koren et al. (1991) Ann. Intern. Med. 114:345-352). At the molecular level, pathological hypertrophy is associated with re-induction of the so-called fetal gene program in which the fetal isoforms of genes responsible for regulating cardiac contractility and calcium handling (e.g. .beta.-MHC) are upregulated (Frey et al. (2004), supra; Frey et al. (2003), supra); Olson (2004) Nat. Med. 10:467-474; Iemitsu et al. (2001) Am. J. Physiol. Regul. Integr. Comp. Physiol. 281:R2029-2036). At the cellular level, the main characteristics of ventricular hypertrophic growth are enhanced protein synthesis and an increase in size of cardiomyocytes (Frey et al. (2004), supra; Frey et al. (2003), supra). As pathologic hypertrophy progresses, these changes in molecular and cellular phenotypes are accompanied by an increase in apoptosis, fibrosis, chamber dilation, and decreased systolic function (Frey et al. (2004), supra).
Heart failure is associated with high morbidity as well as significant mortality. The clinical syndrome of heart failure is the result of heterogeneous myocardial or vascular diseases, and is defined by insufficiency to maintain blood circulation throughout the body. Despite significant advances in the clinical management of heart failure, conventional therapies are ultimately ineffective in many patients who progress to advanced heart failure. In these cases, implantation of left ventricular assist devices (LVAD) and/or heart transplantation can be the only viable options.
In view of the foregoing, there is a need to develop effective treatments for various cardiovascular disorders. In this disclosure, novel therapies to treat cardiovascular disorders, such as pulmonary hypertension, pulmonary hypertension-associated heart failure, and cardiomyopathies, are described.